title: Reduction-cleavable polymeric vesicles with efficient glutathione-mediated drug release behavior for reversing drug resistance.
abstract: In the treatment of cancer, multidrug resistance (MDR) has been the major obstacle to the success of chemotherapy. The underlying mechanism relies on the overexpression of drug-efflux transporters that prevent the intracellular transport of the drug. In this study, reduction-cleavable vesicles were designed and developed with efficient glutathione-mediated drug-release behavior for reversing drug resistance. Polymeric vesicles were self-assembled from triblock copolymers with disulfide-bond-linked poly(ethylene glycol) (PEG) and poly(ε-benzyloxycarbonyl-L-lysine) (PzLL). Observations from transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM) outline an obvious hollow structure surrounded by a thin outer layer, indicating the successful formation of the vesicles. Using fluorescently detectable doxorubicin hydrochloride (DOX·HCl) as the model drug, a significant acceleration of drug release regulated by glutathione (GSH) was found (>3-fold difference). Upon incubation of the DOX·HCl-loaded polymeric vesicles with the HeLa cervical cancer cell line exposed to glutathione, an enhanced nuclear accumulation of DOX·HCl was observed, elicited by the preferred disassembly of the vesicle structure under reducing conditions. Importantly, by using the gemcitabine hydrochloride (GC·HCl)-resistant breast cancer cell line MDA-MB-231, it was found that cell viability was significantly reduced after treatment with GC·HCl-loaded polymeric vesicles, indicating that these vesicles can help to reverse the drug resistance.
authors.affiliation: The Institute for Biomedical Engineering and Nano Science, School of Materials and Engineering, Tongji University , Shanghai 200092, P. R. China.
authors.forename: Tianbin
authors.initials: T
authors.lastname: Ren
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Menghong
authors.initials: M
authors.lastname: Jia
authors.forename: Haiqing
authors.initials: H
authors.lastname: Dong
authors.forename: Yongyong
authors.initials: Y
authors.lastname: Li
authors.forename: Zhouluo
authors.initials: Z
authors.lastname: Ou
mesh_terms: D004317:Doxorubicin / Q000008:administration & dosage; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005978:Glutathione / Q000008:administration & dosage / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D046529:Microscopy, Electron, Transmission; D009369:Neoplasms / Q000188:drug therapy*; D011108:Polymers / Q000737:chemistry
chemical_list: D011108:Polymers; D004317:Doxorubicin; D005978:Glutathione